Zileuton is chemically known as (±)-N-hydroxy-N-(1-benzo-[b]-thien-2-ylethyl)urea and is mentioned below.

Zileuton is commercially available in USA under the brand name of “Zyflo” an oral tablet for the prophylaxis and chronic treatment of asthma.
Zileuton was first disclosed in the U.S. Pat. No. 4,873,259 (hereinafter read as US '259). The Patent US '259 describes the below mentioned scheme for the preparation of Zileuton.

The aforementioned process employs Pyridine-Borane Complex that is toxic and expensive. Excessive reducing agent required to reduce the oxime increases the cost on a large scale. The U.S. Pat. No. 6,080,874 discloses an alternative process for the preparation of Zileuton in a single step, comprising reacting 1-Benzo[b]thiophen-2-ylethanol of formula-II with hydroxyurea in presence of an acid as mentioned below.

The process involves the cumbersome purification process due to the high impurity content in Zileuton.
The Indian Patent application IN 1592/KOL/2007 discloses the improved alternate process for the preparation of Zileuton in a single step involving the step of reacting 1-Benzo[b]thiophen-2-ylethanol of formula-II with hydroxyurea in presence of a Lewis acid and Lewis acid is preferably Borontrifluoride diethyletherate.

The Zileuton formed in acidic condition during the reaction of 1-Benzo[b]thiophen-2-ylethanol of formula-II with hydroxyurea results in the below mentioned impurities.

These impurities are difficult to remove from the final Zileuton and also decrease the yield of the final API.
The other process for the preparation of Zileuton disclosed in the publication of Stewart and Brooks in Journal of Organic Chemistry. 1992, 57, 5020-5023, involves the steps of reacting 1-Benzo[b]thiophen-2-ylethanol formula-II with N,O-bis(phenoxycarbonyl)-hydroxylamine in the presence of diisopropylazodicarboxylate (DIAD) and triphenylphosphine to obtain N,O-bis(phenoxycarbonyl)-N-(1-benzo[b]thien-2-yl-ethyl)-hydroxylamine; followed aminolysis in t-butanol as depicted below.

This process is difficult to perform in large scale and the resulting product has to be purified by chromatography to get pure Zileuton. Further reagents such as diisopropylazodicarboxylate and triphenylphosphine are not suitable for large scale preparations.
The publication Heterocycles, vol-53, No-5, 2000, pages 1175-1182 discloses a reaction 1-Benzo[b]thiophen-2-ylethanol of formula-II with phenol in the presence of Boron trifluoride-diethyletherate as depicted below,

The chromatographic purification of the resulted compound afforded 56% yield and the reactions with similar compounds did not provide desired results.
The Indian Patent application IN 2307/CHE/2007 discloses the preparation for the preparation of Zileuton in two steps involving (1) reaction of 1-Benzo[b]thiophen-2-ylethanol of formula-II with N-(phenoxycarbonyl)-hydroxylamine in presence of hydrochloric acid in toluene to form an intermediate of formula-IV and (2) aminolysis of intermediate of formula-IV in methanol to obtain Zileuton.

The reaction of 1-Benzo[b]thiopen-2-ylethanol of formula-II with N-(phenoxycarbonyl)-hydroxylamine in presence of hydrochloric acid in toluene at a temperature of 50-55° C. for 5 hrs causes acid degradation of the intermediate of formula-V that decrease the yield of the product.
Therefore, there exists a need for a novel process for the preparation of Zileuton that is simple and efficient in large scale and does not require cumbersome purification of the final API.